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The discovery of sulphonamides

In 1932, Gehard Domagk began a study of a bright red dye called Protosil, it was found that it caused a remarkable cure of streptococcal infections in mice (in vivo). However it was in active in on bacterial cultures (in vitro) (Fullerton, 1998). Domagk's studies continued on Protosil, and in 1933 the first of many human cures of severe staphylococcal septicaemias was reported. He was awarded .the Nobel Prize for medicine and physiology in 1939

Protosil's inactivity in vitro, but excellent activity in vivo attracted much attention. It was not until 1935 the activity of sulphonamides was discovered by Trefouel and coworkers, they reported their conclusions form a structure activity study of sulphonamide azo dyes, that the azo linkage was metabolically broken to release the active ingredient, sulphanilamide (Kucers et al, 1997). Their findings were confirmed by Fuller, in which sulphanilamide was isolated from the blood and urine of .)patients treated with Protosil (Fullerton, 1998

Following the dramatic success of Protosil, a cascade of sulphanilamide derivatives began to be synthesised and tested, by 1948 more than 4500 existed, but only about two dozen actually have been used in clinical practice. The sulpha drugs have proven to be ineffective against certain infections such as Salmonella (Patrick, 2001).

Other problems such as toxicity observed in some patients and the evolution of sulphanilamide-resistant bacterial strains, resulted in them being superseded by penicillin. Only a few sulphonamides are extensively used today, for infections in patient with AIDS, urinary tract infections .)and burn therapy (Fullerton, 1998

The role of sulphonamides The sulphonamides interfere with bacterial folate metabolism. In order for purine synthesis to occur, tetrahydrofolate (THF) is a requirement. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para aminobenzoic acid (PABA) is catalysed by .dihydropteroate synthase

Dihydrofolate is further reduced to THF by dihydrofolate reductase. Microorganisms require extracellular PABA to form folic acid. Sulphonamides are analogues of PABA hence they take the place of PABA. They then competitively inhibit dihydrofolate synthase resulting in an accumulation of PABA and .)deficient THF formation (van Boxtel, 2001 The action of sulphonamides is bacteriostatic